Cervical cancer affects approximately 13,000 women per year in the United States and more than 400,000 women worldwide. Ninety percent of cervical cancers contain the high risk HPV DNA strains 16 and 18 (“HPV-16” and “HPV-18,” respectively). By contrast, low risk HPVs, such as HPV-6 and HPV-11, rarely develop into cancer. The presence of low risk and high risk HPVs are identified through the use of the polymerase chain reaction (“PCR”) or the Hybrid Capture® II HPV Test (“HC II HPV Test”; Digene Corp., Gaithersburg, Md.)
The Papanicolaou (“Pap”) smear assesses a patient's risk for cervical cancer by testing for the presence of squamous intraepithelial lesions (“SILs”) on the cervix. The Pap smear has been the standard of care in the U.S. for over 50 years, resulting in a 74% decline in deaths due to cervical cancer. The Pap smear, however, is not without its shortcomings; in particular, errors in cervical sampling and interpretation contribute to a Pap smear sensitivity of only 58%. Hakama, Screening for Cervical Cancer, CANCER TREND RES. 86:41-49 (1996); Nanda et al., Accuracy of the Papanicolaou Test in Screening for and Follow-up of Cervical Cytologic Abnormalities, ANN. INTERN. MED. 132:810-819 (2000). In 1996, the Food and Drug Administration approved the ThinPrep® Pap Test (Cytec Corp., Marlborough, Mass.) as an alternative to the conventional Pap smear for the screening of SILs. The ThinPrep Pap Test screens for SILs using liquid based cytology (“LBC”) with automated monolayer slide production. The use of LBC has resulted in an increase in adequate specimens and the detection of SILs; however, LBC samples have a sensitivity of only 80%. Corkill et al., Specimen Adequacy of the ThinPrep Sample Preparations in a Direct-to-Vial Study, ACTA CYTOL. 41:39-44 (1997); Wilbur et al., Clinical Trials of the CYTORICH Specimen-Preparation Device for Cervical Cytology, ACTA CYTOL. 41:24-29 (1997).
While the life cycle of HPV would indicate that women with high risk HPVs will develop either low grade SILs (“LGSILs,” i.e., SILs from an early pre-malignant lesion) or high grade SILs (“HGSILs,” i.e., SILs from an advanced pre-malignant lesion) and progress to cancer while women with low risk HPVs will not; in reality, only a minority of women infected with high risk HPVs and exhibiting either LGSILs or HGSILs will progress to cancer. The following table shows the rate of regression and progression of women diagnosed via Pap smear or LBC with ASCUS (abnormal squamous cells of undetermined significance), LGSILS, and HGSILs (from Melnikow et al., Natural History of Cervical Squamous Intraepithelial Lesions: A Meta-Analysis, J. OBSTET. GYNECOL. 92:727-735 (1998); see also, Woodman et al., Natural History of Cervical Human Papillomavirus Infection in Young Women: A Longitudinal Cohort Study, LANCET 357:1831-1836 (2001)):
PROGRESSIONPROGRESSIONTO HIGHERTO INVASIVEREGRESSIONGRADE OVERCANCER OVERCYTOLOGYTO NORMAL24 MONTHS24 MONTHSASCUS68% 7%0.25%LGSIL47%21%0.15%HGSIL35%23%1.44%
As the data in the foregoing table demonstrates, the majority of women diagnosed with ASCUS, LGSILS, and HGSILs do not progress to cancer; accordingly, the traditional Pap smear and LBC test, both of which merely identify the presence abnormal SILs are not effective tests to distinguish benign lesions from lesions with malignant potential. Similarly, because the majority of women diagnosed with ASCUS, LGSILS, and HGSILs are usually infected with a high risk HPV, it follows that the identification of infection with a high risk HPV is also not a biologically relevant indicator for cervical cancer detection. There is therefore, a need in the art for a more highly sensitive method by which to screen for cervical cancer.